Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles

Introduction  

Triple-negative breast cancers (TNBCs) are characterised by lack of expression of hormone receptors and epidermal growth factor receptor 2 (HER-2). As they frequently express epidermal growth factor receptors (EGFRs), anti-EGFR therapies are currently assessed for this breast cancer subtype as an alternative to treatments that target HER-2 or hormone receptors. Recently, EGFR-activating mutations have been reported in TNBC specimens in an East Asian population. Because variations in the frequency of EGFR-activating mutations in East Asians and other patients with lung cancer have been described, we evaluated the EGFR mutational profile in tumour samples from European patients with TNBC.     

Colibactin-positive Escherichia coli induce a procarcinogenic immune environment leading to immunotherapy resistance in colorectal cancer

Colibactin-producing E. coli (CoPEC) are frequently detected in colorectal cancer (CRC) and exhibit procarcinogenic properties. Because increasing evidence show the role of immune environment and especially of antitumor T-cells in CRC development, we investigated the impact of CoPEC on these cells in human CRC and in the APC^Min/+ mice colon. T-cell density was evaluated by immunohistochemistry in human tumors known for their CoPEC status. APC^min/+ mice were chronically infected with a CoPEC strain (11G5). Immune cells (neutrophils and T-cell populations) were then quantified by immunofluorescent staining of the colon. The quantification of lymphoid populations was also performed in the mesenteric lymph nodes (MLNs). Here, we show that the colonization of CRC patients by CoPEC is associated with a decrease of tumor-infiltrating T lymphocytes (CD3⁺ T-cells). Similarly, we demonstrated, in mice, that CoPEC chronic infection decreases CD3⁺ and CD8⁺ T-cells and increases colonic inflammation. In addition, we noticed a significant decrease in antitumor T-cells in the MLNs of CoPEC-infected mice compared to that of controls. Moreover, we show that CoPEC infection decreases the antimouse PD-1 immunotherapy efficacy in MC38 tumor model. Our findings suggest that CoPEC could promote a procarcinogenic immune environment through impairment of antitumor T-cell response, leading to tumoral resistance to immunotherapy. CoPEC could thus be a new biomarker predicting the anti-PD-1 response in CRC.     

Therapy-related acute myeloid leukemia: role of DNA repair

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.     

Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients

Purpose

Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis.

Methods

We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects.

Results

Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440?±?107?mg/day) compared with wild-type and CYP2C19*17-allele carriers (633?±?197?mg/day and 600?±?193?mg/day, respectively, P?CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P?CYP2C19 status.

Conclusions

In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.     

Robust extraction of covariate information to improve estimation efficiency in randomized trials

In randomized trials, investigators typically rely upon an unadjusted estimate of the mean outcome within each treatment arm to draw causal inferences. Statisticians have underscored the gain in efficiency that can be achieved from covariate adjustment in randomized trials with a focus on problems involving linear models. Despite recent theoretical advances, there has been a reluctance to adjust for covariates based on two primary reasons: (i) covariate-adjusted estimates based on conditional logistic regression models have been shown to be less precise and (ii) concern over the opportunity to manipulate the model selection process for covariate adjustments to obtain favorable results. In this paper, we address these two issues and summarize recent theoretical results on which is based a proposed general methodology for covariate adjustment under the framework of targeted maximum likelihood estimation in trials with two arms where the probability of treatment is 50%. The proposed methodology provides an estimate of the true causal parameter of interest representing the population-level treatment effect. It is compared with the estimates based on conditional logistic modeling, which only provide estimates of subgroup-level treatment effects rather than marginal (unconditional) treatment effects. We provide a clear criterion for determining whether a gain in efficiency can be achieved with covariate adjustment over the unadjusted method. We illustrate our strategy using a resampled clinical trial dataset from a placebo controlled phase 4 study. Results demonstrate that gains in efficiency can be achieved even with binary outcomes through covariate adjustment leading to increased statistical power.     

Prevalence and predictors of smoking in "smoke-free" bars. Findings from the International Tobacco Control (ITC) Europe Surveys

National level smoke-free legislation is implemented to protect the public from exposure to second-hand tobacco smoke (SHS). The first aim of this study was to investigate how successful the smoke-free hospitality industry legislation in Ireland (March 2004), France (January 2008), the Netherlands (July 2008), and Germany (between August 2007 and July 2008) was in reducing smoking in bars. The second aim was to assess individual smokers' predictors of smoking in bars post-ban. The third aim was to examine country differences in predictors and the fourth aim was to examine differences between educational levels (as an indicator of socioeconomic status). This study used nationally representative samples of 3147 adult smokers from the International Tobacco Control (ITC) Europe Surveys who were surveyed pre- and post-ban. The results reveal that while the partial smoke-free legislation in the Netherlands and Germany was effective in reducing smoking in bars (from 88% to 34% and from 87% to 44%, respectively), the effectiveness was much lower than the comprehensive legislation in Ireland and France which almost completely eliminated smoking in bars (from 97% to 3% and from 84% to 3% respectively). Smokers who were more supportive of the ban, were more aware of the harm of SHS, and who had negative opinions of smoking were less likely to smoke in bars post-ban. Support for the ban was a stronger predictor in Germany. SHS harm awareness was a stronger predictor among less educated smokers in the Netherlands and Germany. The results indicate the need for strong comprehensive smoke-free legislation without exceptions. This should be accompanied by educational campaigns in which the public health rationale for the legislation is clearly explained.     

Utility of time-dependent inverse-probability-of-treatment weights to analyze observational cohorts in the intensive care unit

Objective

When analyzing observational databases, marginal structural models (MSMs) may offer an appealing approach to estimate causal effects. We aimed at evaluating MSMs, in accounting for confounding when assessing the benefit of intensive care unit (ICU) admission and on its interaction with patient age, as compared with propensity score (PS) matching.

Study Design and Setting

PS and inverse-probability-of-treatment weights for MSMs were derived from an observational study designed to evaluate the benefit of ICU admission on in-hospital mortality. Only first ICU triages (time-fixed weights) or whole triage history (time-dependent weights) were considered. Weights were stabilized by either the prevalence of the actual treatment or the probability of the actual treatment given baseline covariates. Risk difference (RD) was the main outcome measure.

Results

MSMs with time-dependent weights offered the best reduction in the baseline imbalances as compared with PS matching. No effect of ICU admission on in-hospital mortality was found (RD = 0.010; 95% confidence interval = −0.038, 0.052) with no interaction between age and treatment.

Conclusion

MSMs appear interesting to handle selection bias in observational studies. When confounding evolves over time, the use of time-dependent weights should be stressed out.     

Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy

Background

Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment.

Objective

To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC.

Patients and Methods

For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test.

Results

Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.004), sarcomatoid component (p=0.037), and PD-L1 (p<0.001) after logistic regression. No difference was observed in clinical outcomes.

Conclusion

This study is the first to analyse c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.

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Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial

Purpose

We investigated whether acetaminophen, given at 2?g/day and 3?g/day might potentiate the anticoagulant effect of warfarin.

Methods

Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2?g/day or 3?g/day) or placebo.

Results

The mean maximal INR increase was 0.70?±?0.49 and 0.67?±?0.62 in patients receiving acetaminophen at 2?g/day and 3?g/day, respectively (P?=?0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R ²?=?0.36, P?R ²?=?0.46, P?R ²?=?0.563, P?Conclusion Acetaminophen, at 2?g/day or 3?g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.